This review highlights key advances in diabetic neuropathy (DN) presented at the 2025 annual meetings of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). New studies confirmed the systemic impact of both diabetic peripheral neuropathy (DPN) and diabetic autonomic neuropathy (DAN). Cardiovascular autonomic neuropathy (CAN) was strongly linked with poor glycaemic control, impaired exercise tolerance, and increased risk of heart failure, particularly in patients with silent myocardial infarction. DSPN independently predicted stroke in type 1 diabetes. DN in general was associated with a higher risk of severe mental illness in type 2 diabetes. Therapeutically, dapagliflozin promoted corneal nerve regeneration through anti-inflammatory pathways. Novel biomarkers, such as plasma methylglyoxal, and advanced neuroimaging emerged as promising tools for risk stratification and personalised pain management. Machine learning applied to neuroimaging data identified neural connectivity patterns predictive of treatment response in painful DN. Basic science studies elucidated new mechanisms, including Schwann cell ferroptosis, and a gut-brain axis contributing to neuropathic pain and cognitive decline. Taken together, these findings promote our understanding of DN pathophysiology and therapy.

Diabetes mellitus (DM) and its complications pose a major global health burden, while currently used biomarkers such as HbA1c and microalbuminuria remain limited for early diagnosis and individualized management. Klotho, originally identified as an anti-aging protein, has recently gained increasing attention due to its roles in mineral metabolism, oxidative stress regulation, inflammation, and fibrosis. This review discusses the biological functions of Klotho and its involvement in the pathogenesis of DM, with a particular emphasis on its regulatory mechanisms in glucose metabolism and oxidative stress. We comprehensively summarize recent findings on the role of Klotho in diabetic complications, including diabetic kidney disease, retinopathy, neuropathy, and cardiovascular disease, and highlight evidence on Klotho gene polymorphisms that influence susceptibility to DM and its complications across different populations. Furthermore, we analyze the limitations of current studies, including inconsistent findings on circulating Klotho levels, lack of standardized detection methods, and insufficient large-scale clinical trials. Finally, this review explores the potential of Klotho as both a biomarker and therapeutic target, and outlines future research directions focusing on standardization, mechanistic studies, and translational applications to advance precision medicine in diabetes management.

ABSTRACTBackgroundObesity increases the risk of diabetic peripheral neuropathy (DPN). However, past studies have typically assessed obesity using anthropometric measurements. Our primary aim determined associations between detailed obesity measurements, DPN, and painful DPN (pDPN). Our secondary aim compared the discriminatory capabilities of these measurements.MethodsWe performed a cross‐sectional study of persons with diabetes. Obesity was assessed using anthropometrics, bioelectrical impedance (BIA), abdominal MRIs (aMRI), and/or dual x‐ray absorptiometry (DEXA). Obesity measurements were categorized as measuring general, central, or peripheral obesity, or the central‐peripheral obesity ratio. DPN was defined as Michigan Neuropathy Screening Instrument questionnaire ≥ 4. Within this group, pDPN was defined as bilateral foot pain in the prior 3 months. Areas under receiver operating characteristic curves (AUC) determined discriminatory capabilities of obesity measurements for DPN, stratified by sex.ResultsWe identified 7090 persons with diabetes that completed DPN assessments (mean age: 58.4, 39.6% female), of which 100.0% completed anthropometrics, 98.4% completed BIA, 3.9% completed aMRI, and 2.3% completed DEXA. 1271 (17.9%) had DPN with 28.1% experiencing pDPN. Logistic regression revealed 13/13 anthropometric, 27/29 BIA, 21/34 DEXA, and 8/14 aMRI measurements associated with DPN, but none associated with pDPN. For males, median AUCs for DPN were similar regardless of location (central: 0.88, 0.89, general: 0.89, peripheral: 0.88, central–peripheral ratio: 0.87), whereas for females, central obesity (0.92) had the largest AUC for DPN, followed by general (0.88), peripheral (0.84), and central–peripheral obesity ratio (0.78).ConclusionsObesity is associated with DPN, but not pDPN. For males, obesity distribution did not differentially discriminate DPN, whereas for females, central obesity best discriminated DPN.

ABSTRACTBackgroundInflammation is increasingly recognized in the pathogenesis of diabetic neuropathy (DN). Circulating miR‐27a‐3p levels are closely related to inflammation and increased in patients with diabetic nephropathy and retinopathy. miR‐27a‐3p has a predicted binding site in the 3 UTR of Netrin‐1 mRNA, an anti‐inflammatory nerve growth factor whose levels correlate with small nerve fiber loss in patients with DN.MethodsEighty‐two participants with (DN+) and without (DN‐) small nerve fiber damage and 45 healthy controls underwent measurement of plasma miR‐27a‐3p, PBMC levels of NF‐kB and NLRP3, serum Netrin‐1, TNFα, IL‐1β, and IL‐10 levels.ResultsCorneal nerve fiber density (CNFD), branch density (CNBD), and fiber length (CNFL) were significantly lower in the DN‐ and DN+ groups compared to controls (p < 0.001). Plasma miR‐27a‐3p and PBMC NF‐kB and NLRP3 expression were significantly higher in the DN+ group, and miR‐27a‐3p identified DN+ with an area under the curve (AUC) of 89%. Serum Netrin‐1 and IL‐10 levels were lower, while TNFα and IL‐1β levels were higher in the DN+ group. miR‐27a‐3p levels correlated negatively with CNFL and Netrin‐1 and positively with NF‐kB and NLRP3.ConclusionmiR‐27a‐3p levels are elevated in subjects with DN and correlate with markers of inflammation, Netrin‐1, and corneal nerve loss. miR‐27a‐3p could be a biomarker for DN, and miR‐27a‐3p/Netrin‐1 crosstalk may be a promising therapeutic target for DN.

Diabetic retinopathy (DR) and diabetic peripheral neuropathy (DPN) are among the most prevalent complications of diabetes mellitus (DM), both of which stem from microvascular complications and are believed to have a shared underlying pathophysiology. A notable challenge is that patients may go unnoticed for either condition by their treating physician, given that these complications typically fall under different medical specialties. Consequently, this study aimed to investigate the clinical correlation between the severity of DR and DPN and explore their associations with glycemic variability and the levels of glycated hemoglobin (HbA1c). This is a hospital-based cross-sectional observational study involving 156 patients attending the ophthalmology outpatient department and the inpatient department at a tertiary care hospital in rural South India over a period of 2 years. There was an increase in the severity of DR with increasing duration of DM among patients (P < 0.001). The proportion of patients with DPN notably increased with increasing severity of DR among the patients (P < 0.001). Notably, the number of patients with DR and DPN changes increased with increasing glycemic values. These findings suggest a statistically significant association between DR and DPN and glycemic control. This study revealed a positive correlation between the severity of DR and the presence of DPN, along with an association with HbA1c variability. This underscores the importance of interdisciplinary collaboration for comprehensive evaluation and management.

Topical application of the antimuscarinic pirenzepine increased lower limb nerve fibre density in a phase 2a study in type 2 patients with diabetes with peripheral neuropathy.

Background: Diabetic peripheral neuropathy (DPN) is one of the most common and debilitating complications of diabetes mellitus, for which current therapies do not prevent nerve degeneration. Chitosan, a biocompatible polysaccharide with antioxidant, anti-inflammatory, and lipid-lowering properties, may exert direct neuroprotective effects. This study evaluated the impact of oral administration of chitosan on peripheral nerve function and structure in a murine model of streptozotocin (STZ)-induced diabetes. Methods: Male C57BL/6 mice were divided into three groups: Sham, untreated diabetics (T1DM) and diabetics treated with chitosan (150 mg/kg/day, 12 weeks). Metabolic, behavioral (Open Field), nociceptive (Von Frey, Tail-Flick), electrophysiological (compound motor action potential—CMAP) and histological (intraepidermal nerve fiber density—IENF) parameters were analyzed. Results: Chitosan did not significantly modify blood glucose (p = 0.3366), but showed favorable metabolic effects, reducing LDL cholesterol in T1DM+Chitosan vs. T1DM mice (43.75 ± 5.62 mg/dL vs. 82.75 ± 7.65 mg/dL, p &lt; 0.0001) as well as triglycerides (103.5 ± 12.8 mg/dL vs. 175.5 ± 22.8 mg/dL, p &lt; 0.0001). In nociceptive tests, chitosan ameliorated thermal hyperalgesia (Tail-Flick: T1DM 1.25 ± 0.19 s vs. T1DM+Chitosan 1.54 ± 0.16 s; p = 0.0188) and mechanical allodynia (Von Frey: T1DM 0.16 ± 0.07 g vs. T1DM+Chitosan 0.38 ± 0.15 g, p = 0.0103). Electrodiagnostically, chitosan improved CMAP amplitude (T1DM 5.756 ± 0.706 mV vs. T1DM + Chitosan 6.756 ± 0.760 mV, p = 0.0409) and reduced CMAP duration (3.161 ± 0.217 ms vs. 2.900 ± 0.080 ms, p = 0.0273). Histologically, IENF density significantly increased in the treated group (0.01991 ± 0.00246 vs. 0.01512 ± 0.00253 in T1DM; p = 0.0200). Conclusions: Oral administration of chitosan confers functional and structural neuroprotection in STZ-induced diabetic neuropathy despite persistent hyperglycemia.

Diabetes mellitus is a metabolic disease marked by insulin resistance and poor regulation of glucose, which results in hyperglycemia and a host of complications, the most common and crippling of which is diabetic neuropathy. This study assessed the influence of age, gender, Body Mass Index (BMI) and Plantar Arch Index (PAI) on physical function in subjects with diabetic neuropathy using a multiple linear regression model. The study recruited 75 subjects with diabetes mellitus and screened for diabetic neuropathy using the Michigan Neuropathy Screening Instrument. The Berg Balance Scale was utilised to assess balance and the ability to rise from a chair without hand support. Subjects’ BMI, PAI (using the Staheli PAI), and physical function (using the 5 times Sit-to-Stand (STS) test) were recorded for analysis. Regression analysis indicated that age and BMI significantly predict Sit-to-Stand performance, with pvalues of 0.000 and 0.015, respectively. Age had the strongest influence (Beta = 0.426), followed by BMI (Beta=0.262), indicating that older age and higher BMI are associated with longer task completion times. PAI (Right) had a nearly significant positive effect (p=0.055), whereas PAI (Left) and gender (Female) were not significant predictors, with pvalues of 0.817 and 0.739, respectively. The model accounted for approximately 33.6% of the variance in Sit- to-Stand performance, with an overall significant F-statistic (p&lt;0.001). Major Findings: The findings highlight that age and BMI significantly affect physical function, with older age and higher BMI linked to longer completion times for the 5 times STS test. Although gender and PAI showed limited predictive value, the overall results emphasise the need for comprehensive interventions to address age-related functional decline and obesity. These insights contribute to understanding factors affecting diabetic neuropathy, guiding future research and clinical practice.

This study aims to investigate the relationship between blood glucose levels and tingling sensation in the feet among individuals with suspected diabetic neuropathy using the Chi-Square and Spearman correlation approach. A cross-sectional design was applied involving 100 participants aged 35–65 years selected through purposive sampling. Data were collected using structured questionnaires and fasting blood glucose tests, followed by statistical analysis using SPSS. Results showed a significant association between elevated blood glucose levels and the presence of tingling sensations (p &lt; 0.05). Spearman's test indicated a strong positive correlation (r = 0.682), suggesting that as glucose levels increase, the likelihood of tingling sensations also rises. These findings support the hypothesis that persistent hyperglycemia contributes to peripheral nerve damage, potentially leading to diabetic neuropathy. This research highlights the importance of early detection and glycemic control as preventive measures. Further longitudinal studies are recommended to explore causal mechanisms and clinical interventions.

Background: Type 2 diabetes mellitus (T2DM) is a chronic, progressive metabolic disorder marked by insulin resistance and progressive β-cell dysfunction. Early diagnosis is critical to preventing long-term complications, including cardiovascular disease and diabetic neuropathy. Conventional diagnostic techniques, such as blood sampling, are invasive and require significant resources. Saliva, a non-invasive and easily accessible biofluid, may contain biomarkers indicative of systemic metabolic changes. Methods: This case-control study evaluated salivary levels of glucose, interleukin-6 (IL-6), and alpha-amylase in 30 newly diagnosed T2DM patients and 30 age- and gender-matched healthy controls. Unstimulated saliva samples were collected, processed, and analyzed using enzymatic and ELISA-based methods. Data were assessed using independent t-tests and Receiver Operating Characteristic (ROC) curve analysis. Results: T2DM patients showed significantly higher salivary IL-6 (12.8 ± 3.1 pg/mL and 6.3 ± 2.2 pg/mL, respectively) and glucose (10.2 ± 2.7 mg/dL and 5.1 ± 1.8, respectively) compared to controls. Salivary amylase levels showed no significant difference (p = 0.28). ROC curve analysis demonstrated that IL-6 had the highest diagnostic accuracy (AUC = 0.86), followed by glucose (AUC = 0.84). Alpha-amylase exhibited limited diagnostic utility (AUC = 0.63). Conclusions: Silvery IL-6 and glucose appear to be promising non-invasive biomarkers for the early detection of T2DM. While alpha-amylase alone lacks sufficient diagnostic value, it may have adjunctive utility when combined with other markers in broader panels. These findings support the potential of saliva-based diagnostics in diabetes screening.

Diabetes mellitus (DM), a globally prevalent metabolic disease, affects the nervous system through multiple mechanisms, leading to cranial neuropathies. Tolosa-Hunt syndrome (THS) is a rare disorder that, when occurring in diabetic patients, may present with clinical manifestations that overlap with diabetic cranial neuropathy (DCN), increasing the risk of misdiagnosis and delaying corticosteroid treatment. This study aims to systematically analyze the clinical characteristics of THS in diabetic patients and explore optimal management strategies. This study conducted a retrospective analysis, integrating data from previously published cases and cases diagnosed at our center. Inclusion criteria were based on the diagnostic standards for THS outlined in the ICHD-3, while cases with other potential causes of headache and ophthalmoplegia were excluded. Data collected included baseline characteristics, clinical manifestations, treatment regimens, and therapeutic outcomes. Statistical analysis was performed using Fisher's exact test, t-test, and Wilcoxon rank-sum test. A total of 19 cases of diabetes-associated THS were included (11 males, 8 females), with males presenting at a significantly younger age than females (P = 0.041). All patients experienced severe headaches, 89.47% had ptosis, 94.73% exhibited ophthalmoplegia, and 15.79% presented with facial sensory disturbances. Eight patients were initially misdiagnosed with DCN and received neurotrophic therapy without improvement, but they responded rapidly to corticosteroid treatment. All patients showed significant symptom improvement within six days of corticosteroid administration. Methylprednisolone and dexamethasone demonstrated therapeutic effects comparable to prednisone, though symptom resolution was slightly delayed in the prednisone group. The clinical features of diabetes-associated THS include severe headache, ptosis, and ophthalmoplegia, which can be easily confused with DCN. Corticosteroid therapy demonstrated high efficacy in this cohort. Clinicians should consider the possibility of THS in diabetic patients presenting with ptosis and ophthalmoplegia to avoid misdiagnosis and ensure timely corticosteroid treatment, thereby improving patient outcomes.

To investigate the impact of diabetic neuropathy on operative bimalleolar or trimalleolar ankle fracture outcomes when compared with both patients who are nondiabetic and patients who are diabetic without neuropathy. . Retrospective comparative study. TriNetX research network, a global health-collaborative clinical research platform comprising deidentified electronic health records from health care organizations across the United States. The TriNetX research network was queried for all patients with an operative bimalleolar or trimalleolar ankle fracture (OTA/AO 44) from 2005 to 2022. From this population, subgroups were formed based on diabetes status and the presence of diabetic neuropathy. Patients with diabetic neuropathy were compared with both patients who are nondiabetic and patients with diabetes. Propensity score matching (1:1) was performed to match patients based on demographics and comorbidities across groups, including severity of diabetes by A1C. After matching, logistic regression was performed to calculate risk ratios and assess differences in postoperative medical and surgical complications between patients who are neuropathic and patients who are nondiabetic, and between patients who are neuropathic and patients who are diabetic. Included were 115,162 patients with ankle fracture; 94,111 (81.7%) patients without diabetes, 13,741 (12%) patients with diabetes but without diabetic neuropathy, and 7310 (6.3%) patients with diabetic neuropathy. When compared with patients without diabetes, patients with diabetic neuropathy had increased risk of 2-year malunion/nonunion (RR 1.79; P < 0.001), implant infection (RR 2.12; P < 0.001), and amputation (RR 8.01; P < 0.001). When compared with patients with diabetes, but without neuropathy, patients with diabetic neuropathy again had significantly higher odds of implant failure (RR 2.00; P < 0.001), malunion/nonunion (RR 2.35; P < 0.001), and infection (RR 2.25; P < 0.001). This study found that patients with diabetic neuropathy had higher odds of postoperative complications, such as malunion/nonunion, infection, and amputation, after surgical fixation of ankle fractures than patients who are nondiabetic and patients who are diabetic without neuropathy. Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Effectiveness of 10.6-μm laser therapy for diabetic peripheral neuropathy: A double-blind, randomized controlled trial.

Mechanism-driven multitarget therapeutics for diabetic peripheral neuropathy.

A study protocol on experiences and outcomes of neural mobilization and high intensity laser therapy in individuals with chronic sensorimotor diabetic peripheral neuropathy.

The online version contains supplementary material available at 10.1007/s13205-025-04580-3.

Type 2 diabetes mellitus is a chronic metabolic condition that may cause diabetic neuropathy, a debilitating complication driven by chronic hyperglycemia, lipid imbalance, oxidative stress and persistent inflammation. In this study, we investigated the neuroprotective potential of eucalyptol in a streptozotocin-induced rat model of diabetic neuropathy. We found that eucalyptol treatment significantly reduced thermal and mechanical hypersensitivity, lowered blood glucose and glycated hemoglobin, improved insulin levels and favorably regulated lipid profiles by decreasing total cholesterol, triglycerides and low-density lipoprotein cholesterol (LDL-C) while increasing high-density lipoprotein cholesterol (HDL-C). Antioxidant defenses were strengthened, as evidenced by elevated superoxide dismutase, catalase and glutathione-S-transferase activities, alongside reduced malondialdehyde levels. Eucalyptol also exhibited anti-inflammatory effects by inhibiting nuclear factor kappa B (NF-κB) activation and lowering tumor necrosis factor-αlpha (TNF-α) and interleukin-6 (IL-6) expression. Histopathological analysis revealed preserved neuronal cytoarchitecture and reduced degeneration in the brain, along with regeneration of β-cells and restoration of islet morphology in the pancreas. Restoration of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), both key neurotrophins supporting neuronal growth and survival, reflected enhanced neuronal survival and regeneration, further supported by electron microscopic evidence of sciatic nerve repair and remyelination. Collectively, we conclude that eucalyptol provided neuroprotection via glucose-lowering, antioxidant, anti-inflammatory and neurotrophic actions, highlighting its therapeutic potential.

Autonomic symptom burden, comorbidities and quality of life in women with Hypermobility Spectrum Disorders and hypermobile Ehlers-Danlos syndrome.

Computationally guided design and synthesis of pyrimidine-oxazole hybrids as novel antidiabetic agents: kinetic and molecular interaction studies.

Multi-level intervention of Tangluoning on mitochondrial thioredoxin deficiency in Schwann cells ameliorates diabetic peripheral neuropathy